The neocortex, the largest and most complex brain structure, is unique to mammals. It is responsible for sensory perception and cognition, as well as control of our motor systems. In its tangential dimension, the neocortex is organized into subdivisions referred to as "areas" that are distinguished from one another by major differences in their cytoarchitecture and chemoarchitecture, thalamocortical axon (TCA) input and layer 5 and 6 output connections, and patterns of gene expression. These attributes form a specific combination of properties unique for each area, and together with unique combinations of gene expression, determine the functional specializations that characterize and distinguish areas in the adult. The first transcription factor shown to potentially influence arealization was only identified a decade ago. Although of inarguable importance, the mechanisms controlling arealization of the neocortex remain sketchy and controversial, and are largely limited to generalized axial changes in the size and position of primary areas. Here we propose a series of aims to address specific hypotheses on the requirements of certain regulatory genes to specify the identities and properties of cortical areas in the progenitors that generate them. These studies will break new ground, generate novel insights, and revise and correct misconceptions. The studies include determining the specific mechanisms and transcription factors that are required to specify the primary visual area, V1, redundancy in their function, and limits in their action across the cortical hemisphere. We will also address for the first time the genetic mechanisms involved in the specification of higher order areas and test specific hypotheses on these mechanisms. We will reassess roles for Pax6 is arealization, and use its function as a model for studying the effects of specification of area field size on the representation of the sensory periphery within a cortical area, and the importance of graded expression of transcription factors on their function in establishing sensory maps and representations. Finally, we will investigate the influence of cortex-intrinsic genetic changes to area patterning on the principal sensory thalamic nuclei that relay sensory input to cortex, and define mechanisms of reverse plasticity that serve to systems-match thalamic nuclei to their target areas, and to re-pattern them through a retrograde interaction with their target area. These studies will be carried out using conditional loss- and gain-of-function genetics in mice, using numerous mouse lines that we have made for this proposal, and will make use of new gene markers developed for higher order areas. Further, the considerable amount of preliminary findings that we present support our hypotheses, and indicate that our findings will lead to the development of new concepts, in some cases challenging and replacing dogma, that will have implications for neocortical development and plasticity. PUBLIC HEALTH RELEVANCE: The neocortex, the largest and most complex component of the mammalian brain, is the center for sensory processing and perception, motor control, and cognitive functions. The neocortex is organized into anatomically and functionally specialized areas, with four modality-specific primary areas, visual, somatosensory, auditory and motor, each anchoring an extensive, hierarchically organized array of higher order areas, and reciprocally connected with principal nuclei in dorsal thalamus that feed sensory information from the periphery to the cortex. This proposal addresses the genetic mechanisms that specify area patterning of the neocortex and the influence of this patterning on subsequent thalamic differentiation.